13 results on '"Battaglin, Francesca"'
Search Results
2. Germline Polymorphisms in Genes Involved in the Antioxidant System Predict the Efficacy of Cetuximab in Metastatic Colorectal Cancer Patients Enrolled in FIRE-3 Trial.
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Hiroyuki Arai, Millstein, Joshua, Yan Yang, Stintzing, Sebastian, Jingyuan Wang, Battaglin, Francesca, Natsuko Kawanishi, Jayachandran, Priya, Soni, Shivani, Wu Zhang, Heinemann, Volker, Lenzi, Heinz-Josef, Arai, Hiroyuki, Yang, Yan, Wang, Jingyuan, Kawanishi, Natsuko, Zhang, Wu, and Lenz, Heinz-Josef
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- 2022
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3. Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy.
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Ryuma Tokunaga, Shu Cao, Naseem, Madiha, Jae Ho Lo, Battaglin, Francesca, Puccini, Alberto, Berger, Martin D., Soni, Shivani, Millstein, Joshua, Wu Zhang, Stintzing, Sebastian, Loupakis, Fotios, Cremolini, Chiara, Heinemann, Volker, Falcone, Alfredo, Lenz, Heinz-Josef, Tokunaga, Ryuma, Cao, Shu, Lo, Jae Ho, and Zhang, Wu
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- 2019
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4. B cell and B cell-related pathways for novel cancer treatments.
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Tokunaga, Ryuma, Naseem, Madiha, Lo, Jae Ho, Battaglin, Francesca, Soni, Shivani, Puccini, Alberto, Berger, Martin D., Zhang, Wu, Baba, Hideo, and Lenz, Heinz-Josef
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B cells are recognized as the main effector cells of humoral immunity which suppress tumor progression by secreting immunoglobulins, promoting T cell response, and killing cancer cells directly. Given these properties, their anti-tumor immune response in the tumor micro-environment (TME) is of great interest. Although T cell-related immune responses have become a therapeutic target with the introduction of immune checkpoint inhibitors, not all patients benefit from these treatments. B cell and B cell-related pathways (CCL19, -21/CCR7 axis and CXCL13/CXCR5 axis) play key roles in activating immune response through humoral immunity and local immune activation via tertiary lymphoid structure (TLS) formation. However they have some protumorigenic works in the TME. Thus, a better understanding of B cell and B cell-related pathways is necessary to develop effective cancer control. In this review, we summarize recent evidences regarding the roles of B cell and B cell-related pathways in the TME and immune response and discuss their potential roles for novel cancer treatment strategies. [ABSTRACT FROM AUTHOR]
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- 2019
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5. Outlooks on Epstein-Barr virus associated gastric cancer.
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Naseem, Madiha, Barzi, Afsaneh, Brezden-Masley, Christine, Puccini, Alberto, Berger, Martin D., Tokunaga, Ryuma, Battaglin, Francesca, Soni, Shivani, McSkane, Michelle, Zhang, Wu, and Lenz, Heinz-Josef
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Epstein-Barr virus associated gastric cancer (EBVaGC) comprises approximately 10% of gastric carcinomas. Multiple factors contribute to tumorigenesis, including EBV driven hypermethylation of tumor suppressor genes, inflammatory changes in gastric mucosa, host immune evasion by EBV and changes in cell cycle pathways. The unique molecular characteristics of EBVaGC, such as programmed death ligand 1 (PD-L1) overexpression, highlight the potential for using EBV as a biomarker for response to immunotherapy. Few studies have reported benefit from immunotherapy in EBV positive cancers, and clinical trials investigating the impact of checkpoint inhibitors in EBVaGC are currently underway. This review provides the most recent updates on molecular pathophysiology, epidemiology, clinical features and treatment advances pertaining to EBVaGC. [ABSTRACT FROM AUTHOR]
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- 2018
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6. Molecular insight of regorafenib treatment for colorectal cancer.
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Arai, Hiroyuki, Battaglin, Francesca, Wang, Jingyuan, Lo, Jae Ho, Soni, Shivani, Zhang, Wu, and Lenz, Heinz-Josef
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Regorafenib is a multi-targeting kinase inhibitor approved for the treatment of metastatic colorectal cancer patients in refractory to standard chemotherapy. Similarly to sorafenib, this agent was originally developed as a RAF1 inhibitor. However, the kinase inhibitory profile is distinct from sorafenib. A broad-spectrum of kinase inhibition induces wide-range drug sensitivity, irrespective of mutation status of major oncogenes. This agent's main therapeutic effects are anti-angiogenesis and the remodeling of tumor microenvironment through several mechanisms of action. The dual blockade of VEGF receptors and TIE2 can lead to both additive anti-angiogenesis effects and the suggestive unique regulation of vessel stability. Additionally, it inhibits molecular escape pathways to VEGF inhibition (e.g., FGF, PIGF, and PDGF signaling), enabling its continuous antiangiogenic effect even in tumors resistant to VEGF inhibitors. Furthermore, regorafenib has the important effect of enhancing anti-tumor immunity via macrophage modulation. Based on this concept, clinical trials have been recently launched for the development of a combination strategy with immune checkpoint inhibitors. Contrary to regorafenib induced clinical benefits and advances in the novel strategy, currently no predictive biomarkers have been identified. In the present review, we revisit and summarize regorafenib's unique mechanisms of action. The review could highlight molecular insights and provide some perspective for the search of predictive biomarkers used in metastatic colorectal cancer patients treated with regorafenib. [ABSTRACT FROM AUTHOR]
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- 2019
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7. Mutational analysis of microsatellite-stable gastrointestinal cancer with high tumour mutational burden: a retrospective cohort study.
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Wang, Jingyuan, Xiu, Joanne, Farrell, Alex, Baca, Yasmine, Arai, Hiroyuki, Battaglin, Francesca, Kawanishi, Natsuko, Soni, Shivani, Zhang, Wu, Millstein, Joshua, Shields, Anthony F, Grothey, Axel, Weinberg, Benjamin A, Marshall, John L, Lou, Emil, Khushman, Moh'd, Sohal, Davendra P S, Hall, Michael J, Liu, Tianshu, and Oberley, Matthew
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GASTROINTESTINAL cancer , *IMMUNE checkpoint inhibitors , *GASTROINTESTINAL stromal tumors , *TUMOR microenvironment , *COHORT analysis , *FISHER exact test - Abstract
Genomic signatures contributing to high tumour mutational burden (TMB-H) independent from mismatch-repair deficiency (dMMR) or microsatellite instability-high (MSI-H) status are not well studied. We aimed to characterise molecular features of microsatellite stable (MSS) TMB-H gastrointestinal tumours. Molecular alterations of 48 606 gastrointestinal tumours from Caris Life Sciences (CARIS) identified with next-generation sequencing were compared among MSS–TMB-H, dMMR/MSI-H, and MSS–TMB-low (L) tumours, using χ2 or Fisher's exact tests. Antitumour immune response within the tumour environment was predicted by analysing the infiltration of immune cells and immune signatures using The Cancer Genome Atlas database. The Kaplan-Meier method and the log-rank test were used to evaluate the impact of gene alterations on the efficacy of immune checkpoint inhibitors in MSS gastrointestinal cancers from the CARIS database, a Memorial Sloan Kettering Cancer Center cohort, and a Peking University Cancer Hospital cohort. MSS–TMB-H was observed in 1600 (3·29%) of 48 606 tumours, dMMR/MSI-H in 2272 (4·67%), and MSS–TMB-L in 44 734 (92·03%). Gene mutations in SMAD2, MTOR, NFE2L2, RB1, KEAP1, TERT , and RASA1 might impair antitumour immune response despite TMB-H, while mutations in 16 other genes (CDC73, CTNNA1, ERBB4, EZH2, JAK2, MAP2K1, MAP2K4, PIK3R1, POLE, PPP2R1A, PPP2R2A, PTPN11, RAF1, RUNX1, STAG2 , and XPO1) were related to TMB-H with enhanced antitumour immune response independent of dMMR/MSI-H, constructing a predictive model (modified TMB [mTMB]) for immune checkpoint inhibitor efficacy. Patients with any mutation in the mTMB gene signature, in comparison with patients with mTMB wildtype tumours, showed a superior survival benefit from immune checkpoint inhibitors in MSS gastrointestinal cancers in the CARIS cohort (n=95, median overall survival 18·77 months [95% CI 17·30–20·23] vs 7·03 months [5·73–8·34]; hazard ratio 0·55 [95% CI 0·31–0·99], p=0·044). In addition, copy number amplification in chromosome 11q13 (eg, CCND1 , FGF genes) was more prevalent in MSS–TMB-H tumours than in the dMMR/MSI-H or MSS–TMB-L subgroups. Not all mutations related to TMB-H can enhance antitumour immune response. More composite biomarkers should be investigated (eg, mTMB signature) to tailor treatment with immune checkpoint inhibitors. Our data also provide novel insights for the combination of immune checkpoint inhibitors and drugs targeting cyclin D1 or FGFs. US National Cancer Institute, Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Gene Gregg Pancreas Research Fund, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Victoria and Philip Wilson Research Fund, Fong Research Project, Ming Hsieh Research Fund, Shanghai Sailing Program, China National Postdoctoral Program for Innovative Talents, China Postdoctoral Science Foundation, National Natural Science Foundation of China. [ABSTRACT FROM AUTHOR]
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- 2023
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8. Genetic variants involved in the cGAS-STING pathway predict outcome in patients with metastatic colorectal cancer: Data from FIRE-3 and TRIBE trials.
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Wang, Jingyuan, Xiao, Yi, Loupakis, Fotios, Stintzing, Sebastian, Yang, Yan, Arai, Hiroyuki, Battaglin, Francesca, Kawanishi, Natsuko, Jayachandran, Priya, Soni, Shivani, Zhang, Wu, Mancao, Christoph, Cremolini, Chiara, Liu, Tianshu, Heinemann, Volker, Falcone, Alfredo, Shen, Lin, Millstein, Joshua, and Lenz, Heinz-Josef
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THERAPEUTIC use of antineoplastic agents , *DNA , *CONFIDENCE intervals , *SINGLE nucleotide polymorphisms , *MULTIVARIATE analysis , *MONOCLONAL antibodies , *METASTASIS , *ALLELES , *COLORECTAL cancer , *CELLULAR signal transduction , *GENE expression , *CANCER patients , *RANDOMIZED controlled trials , *GENOTYPES , *STATISTICAL sampling - Abstract
The activation of stimulator of interferon genes (STING) was reported to enhance cetuximab-mediated natural killer cell activation and dendritic cell maturation. Polymorphisms in genes in the cyclic GMP-AMP synthase (cGAS)-STING pathway may affect innate immune response. Therefore, we hypothesised that genetic variants in the cGAS-STING pathway may predict the efficacy of cetuximab-based treatment in patients with metastatic colorectal cancer. Genomic DNA from blood samples of patients enrolled in FIRE-3 (cetuximab arm, n = 129; bevacizumab arm, n = 107) and TRIBE (bevacizumab arm, n = 215) was genotyped using the OncoArray-500K bead chip panel. Seven selected single nucleotide polymorphisms in 3 genes (cGAS, STING and interferon B1 (IFNB1)) were analysed for the association with overall survival and progression-free survival. In the cetuximab cohort, patients with STING rs1131769 any T allele showed significantly shorter overall survival (36.3 versus 56.1 months) than carriers of C/C in both univariate [hazard ratio (HR) = 2.08; 95% confidence interval (CI): 1.06–4.07; P = 0.03] and multivariate (HR = 2.98; 95% CI: 1.35–6.6; P = 0.0085) analyses; patients carrying IFNB1 rs1051922 G/A and A/A genotype showed a significantly shorter progression-free survival than carriers of G/G allele in both univariate (G/A versus G/G, 10.2 versus 14.1 months, HR = 1.84; 95% CI 1.23–2.76; A/A versus G/G, 10.7 versus 14.1 months, HR = 2.19; 95% CI 0.97–4.96; P = 0.0077) and multivariate analyses (G/A versus G/G, HR = 2; 95% CI 1.22–3.3; A/A versus G/G, HR = 2.19, 95% CI 0.92–5.26, P = 0.02). These associations were not observed in the bevacizumab arm of FIRE-3 or TRIBE. These results suggest for the first time that germline polymorphisms in STING and IFNB1 genes may predict the outcomes of cetuximab-based treatment in patients with metastatic colorectal cancer. • Predictive values of SNPs involved in cGAS-STING pathway were tested. • STING rs1131769 was significantly associated with OS in patients receiving cetuximab-based first-line treatment.IFNB1 rs1051922 was significantly associated with PFS in patients receiving cetuximab-based first-line treatment. • Associations between tested SNPs and bevacizumab efficacy were not significant. [ABSTRACT FROM AUTHOR]
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- 2022
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9. Germ line polymorphisms of genes involved in pluripotency transcription factors predict efficacy of cetuximab in metastatic colorectal cancer.
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Arai, Hiroyuki, Millstein, Joshua, Loupakis, Fotios, Stintzing, Sebastian, Wang, Jingyuan, Battaglin, Francesca, Kawanishi, Natsuko, Jayachandran, Priya, Soni, Shivani, Zhang, Wu, Mumenthaler, Shannon M., Cremolini, Chiara, Heinemann, Volker, Falcone, Alfredo, and Lenz, Heinz-Josef
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THERAPEUTIC use of monoclonal antibodies , *THERAPEUTIC use of antineoplastic agents , *COLON tumors , *DRUG efficacy , *STATISTICS , *DNA , *CONFIDENCE intervals , *SINGLE nucleotide polymorphisms , *ONCOGENES , *EPIDERMAL growth factor receptors , *MULTIVARIATE analysis , *METASTASIS , *GERM cells , *BLOOD collection , *ALLELES , *CELLULAR signal transduction , *CANCER patients , *STEM cells , *GENOMICS , *GENOTYPES , *SURVIVAL analysis (Biometry) , *TRANSCRIPTION factors , *VASCULAR endothelial growth factors , *BEVACIZUMAB ,RECTUM tumors - Abstract
Cancer stem cells (CSCs) are primarily maintained by a network of pluripotency transcription factors (PTFs). Given a close relationship of CSC regulation with epidermal growth factor receptor and vascular endothelial growth factor signalling, we investigated whether single-nucleotide polymorphisms (SNPs) in PTF genes are related to the efficacy of cetuximab and/or bevacizumab in patients with metastatic colorectal cancer (mCRC). Genomic and clinical data from three independent clinical trial cohorts were tested: cetuximab cohort (FOLFIRI/cetuximab arm in FIRE-3, n = 129), bevacizumab cohort 1 (FOLFIRI/bevacizumab arm in FIRE-3, n = 107) and bevacizumab cohort 2 (FOLFIRI/bevacizumab arm in TRIBE, n = 215). Genomic DNA extracted from blood samples was genotyped, and ten SNPs were tested for association with clinical outcomes. In the cetuximab cohort, four SNPs were significantly associated with progression-free survival in univariate analysis: NANOG rs11055767 (any A allele vs C/C, hazard ratio [HR] = 0.62, 95% confidence interval [CI] = 0.42–0.94, p = 0.02), NANOG rs10744044 (any A allele vs G/G, HR = 0.59, 95% CI = 0.39–0.90, p = 0.01), NANOGP8 rs2168958 (any C allele vs A/A, HR = 2.12, 95% CI = 1.36–3.29, p < 0.001) and NANOGP8 rs2279066 (any C allele vs T/T, HR = 1.80, 95% CI = 1.06–1.68, p = 0.03). Multivariate analysis confirmed the significant associations for NANOGP8 rs2168958 and NANOGP8 rs2279066. In either bevacizumab cohort, no significant associations were observed in univariate analysis. Germ line polymorphisms in the PTF genes could be predictive markers for cetuximab in mCRC. • Predictive values of pluripotency transcription factor genes' single-nucleotide polymorphisms (SNPs) were tested. • NANOGP8 rs2168958 and rs2279066 were associated with efficacy of cetuximab. • Associations between tested SNPs and bevacizumab efficacy were not significant. [ABSTRACT FROM AUTHOR]
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- 2021
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10. Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer.
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Arai, Hiroyuki, Yang, Yan, Baca, Yasmine, Millstein, Joshua, Denda, Tadamichi, Ou, Fang-Shu, Innocenti, Federico, Takeda, Hiroyuki, Kubota, Yohei, Doi, Ayako, Horie, Yoshiki, Umemoto, Kumiko, Izawa, Naoki, Wang, Jingyuan, Battaglin, Francesca, Jayachandran, Priya, Algaze, Sandra, Soni, Shivani, Zhang, Wu, and Goldberg, Richard M.
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THERAPEUTIC use of antineoplastic agents , *VASCULAR endothelial growth factor antagonists , *THERAPEUTIC use of monoclonal antibodies , *PREDICTIVE tests , *PROTEIN kinase inhibitors , *BEVACIZUMAB , *GENETIC markers , *COLORECTAL cancer , *DESCRIPTIVE statistics , *RETROSPECTIVE studies , *TREATMENT effectiveness , *METASTASIS , *LONGITUDINAL method , *CANCER chemotherapy , *GENE expression profiling , *DRUG efficacy , *SURVIVAL analysis (Biometry) , *PROGRESSION-free survival , *CONFIDENCE intervals , *HYPOXEMIA - Abstract
CDC37 is a key determinant of client kinase recruitment to the HSP90 chaperoning system. We hypothesized that kinase-specific dependency on CDC37 alters the efficacy of targeted therapies for metastatic colorectal cancer (mCRC). Two independent mCRC cohorts were analyzed to compare the survival outcomes between CDC37 -high and CDC37 -low patients (stratified by the median cutoff values): the CALGB/SWOG 80405 trial (226 and 207 patients receiving first-line bevacizumab- and cetuximab-containing chemotherapies, respectively) and Japanese retrospective (50 refractory patients receiving regorafenib) cohorts. A dataset of specimens submitted to a commercial CLIA-certified laboratory was utilized to characterize molecular profiles of CDC37 -high (top quartile, N = 5055) and CDC37 -low (bottom quartile, N = 5055) CRCs. In the bevacizumab-treated group, CDC37 -high patients showed significantly better progression-free survival (PFS) (median 13.3 vs 9.6 months, hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44–0.79, p < 0.01) than CDC37 -low patients. In the cetuximab-treated group, CDC37 -high and CDC37 -low patients had similar outcomes. In the regorafenib-treated group, CDC37 -high patients showed significantly better overall survival (median 11.3 vs 6.0 months, HR 0.24, 95% CI 0.11–0.54, p < 0.01) and PFS (median 3.5 vs 1.9 months, HR 0.51, 95% CI 0.28–0.94, p = 0.03). Comprehensive molecular profiling revealed that CDC37 -high CRCs were associated with higher VEGFA , FLT1 , and KDR expressions and activated hypoxia signature. CDC37 -high mCRC patients derived more benefit from anti-VEGF therapies, including bevacizumab and regorafenib, but not from cetuximab. Molecular profiles suggested that such tumors were dependent on angiogenesis-relating pathways. • We explored a novel predictive biomarker CDC37 expression in treatment of mCRC. • CDC37 -highly expressed mCRC derived more benefit from bevacizumab and regorafenib. • No significant associations between CDC37 expression and cetuximab efficacy were observed. • The angiogenesis-relating pathways were activated in CDC37 -highly expressed CRC. [ABSTRACT FROM AUTHOR]
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- 2024
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11. The impact of ARID1A mutation on molecular characteristics in colorectal cancer.
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Tokunaga, Ryuma, Xiu, Joanne, Goldberg, Richard M., Philip, Philip A., Seeber, Andreas, Battaglin, Francesca, Arai, Hiroyuki, Lo, Jae Ho, Naseem, Madiha, Puccini, Alberto, Berger, Martin D., Soni, Shivani, Zhang, Wu, Chen, Sting, Hwang, Jimmy J., Shields, Anthony F., Marshall, John L., Baba, Hideo, Korn, W.Michael, and Lenz, Heinz-Josef
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CANCER patients , *CELLULAR signal transduction , *COLON tumors , *IMMUNOHISTOCHEMISTRY , *MEMBRANE proteins , *GENETIC mutation , *MOLECULAR pathology , *RNA , *T cells , *EPIDERMAL growth factor receptors , *DESCRIPTIVE statistics , *SEQUENCE analysis , *SYMPTOMS ,RECTUM tumors - Abstract
ARID1A is a key subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex which regulates dynamic repositioning of nucleosomes to repair DNA damage. Only small pilot studies have evaluated the role of ARID1A mutation in colorectal cancer (CRC). The aim of the present study was to explore the potential impact of ARID1A mutation on clinicopathological and molecular characteristics in CRC. We used integrated data sets of 7978 CRC cases (one data set from a clinical laboratory improvement amendments [CLIA]-certified laboratory and three independent published data sets). The associations of ARID1A mutation with molecular characteristics including immune profile (the status of microsatellite instability [MSI], tumour mutational burden [TMB], programmed death ligand 1 [PD-L1] and estimated infiltrating immune cells), clinicopathological features and related pathways were analysed using next-generation sequencing, RNA sequencing and immunohistochemistry. ARID1A mutant samples had more genomically unstable tumour features (MSI-high and TMB-high) and exhibited more characteristics of a T-cell–inflamed microenvironment (PD-L1 expression and high estimated infiltrating cytotoxic T lymphocytes [CTLs]) than ARID1A wild-type samples in the discovery and validation cohorts. Even ARID1A mutant samples without MSI-high status were TMB-high, had high levels of PD-L1 expression and high estimated infiltrating CTLs. ARID1A mutations were more common with right-sided primary and earlier stage tumours. ARID1A mutant tumours mainly had co-occurring gene mutations related to chromatin modifying, DNA repair, WNT signalling and epidermal growth factor receptor inhibitor resistance pathways, and ARID1A mutations strongly regulated DNA repair pathways. Key genes for chemotherapy/radiotherapy sensitivity were suppressed in ARID1A mutant samples. Our findings may provide novel insights to develop individualised approaches for treatment of CRC based on ARID1A mutation status. • The impact of ARID1A mutations was analysed using 7978 colorectal cancer samples. • ARID1A mutation was linked to immune activation, right-sided tumour and early stage. • ARID1A mutation may be a biomarker for chemotherapy/radiotherapy and targeted therapy. [ABSTRACT FROM AUTHOR]
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- 2020
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12. A polymorphism within the R-spondin 2 gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab: data from FIRE-3 and TRIBE trials.
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Berger, Martin D., Ning, Yan, Stintzing, Sebastian, Heinemann, Volker, Cao, Shu, Zhang, Wu, Yang, Dongyun, Miyamoto, Yuji, Suenaga, Mitsukuni, Schirripa, Marta, Hanna, Diana L., Soni, Shivani, Puccini, Alberto, Tokunaga, Ryuma, Naseem, Madiha, Battaglin, Francesca, Cremolini, Chiara, Falcone, Alfredo, Loupakis, Fotios, and Lenz, Heinz-Josef
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ANTINEOPLASTIC agents , *THERAPEUTIC use of monoclonal antibodies , *ALLELES , *BIOMARKERS , *CANCER patients , *CELLULAR signal transduction , *COLON tumors , *GENETIC polymorphisms , *METASTASIS , *GENETIC mutation , *SURVIVAL analysis (Biometry) , *DISEASE progression , *GENOTYPES ,RECTUM tumors - Abstract
Through enhancement of the Wnt signalling pathway, R-spondins are oncogenic drivers in colorectal cancer. Experimental data suggest that the R-spondin/Wnt axis stimulates vascular endothelial growth factor (VEGF)-dependent angiogenesis. We therefore hypothesise that variations within R-spondin genes predict outcome in patients with metastatic colorectal cancer (mCRC) treated with upfront FOLFIRI and bevacizumab. 773 patients with mCRC enrolled in the randomised phase III FIRE-3 and TRIBE trials and receiving either FOLFIRI/bevacizumab (training and validation cohorts) or FOLFIRI/cetuximab (control group) were involved in this study. The impact of six functional single-nucleotide polymorphisms (SNPs) within the R-spondin 1-3 genes on outcome was evaluated. RAS and KRAS wild-type patients harbouring any G allele of the RSPO2 rs555008 SNP had a longer overall survival compared with those having a TT genotype in both the training (FIRE-3) and validation (TRIBE) cohorts (29.0 vs 23.6 months, P = 0.009 and 37.8 vs 19.4 months, P = 0.021 for RAS wild-type patients and 28.4 vs 22.3 months, P = 0.011 and 36.0 vs 23.3 months, P = 0.046 for KRAS wild-type patients). Conversely, any G allele carriers with KRAS and RAS mutant tumours exhibited a shorter progression-free survival compared with TT genotype carriers, whereas the results were clinically more evident for KRAS mutant patients in both the training and validation cohorts (8.1 vs 11.2 months, P = 0.023 and 8.7 vs 10.3 months, P = 0.009). Genotyping of the RSPO2 rs555008 polymorphism may help to select patients who will derive the most benefit from FOLFIRI/bevacizumab dependent on (K)RAS mutational status. • Markers predicting efficacy of bevacizumab in metastatic colon cancer are warranted. • R-spondins play a role in angiogenesis and progression of colorectal cancer. • R-spondins exert their oncogenic role through activation of the Wnt pathway. • A polymorphism in RSPO2 predicts outcome in patients receiving FOLFIRI/bevacizumab. • Potential to identify patients who will benefit most from FOLFIRI/bevacizumab. [ABSTRACT FROM AUTHOR]
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- 2020
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13. Impact of polymorphisms within genes involved in regulating DNA methylation in patients with metastatic colorectal cancer enrolled in three independent, randomised, open-label clinical trials: a meta-analysis from TRIBE, MAVERICC and FIRE-3.
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Puccini, Alberto, Loupakis, Fotios, Stintzing, Sebastian, Cao, Shu, Battaglin, Francesca, Togunaka, Ryuma, Naseem, Madiha, Berger, Martin D., Soni, Shivani, Zhang, Wu, Mancao, Christoph, Salhia, Bodour, Mumenthaler, Shannon M., Weisenberger, Daniel J., Liang, Gangning, Cremolini, Chiara, Heinemann, Volker, Falcone, Alfredo, Millstein, Joshua, and Lenz, Heinz-Josef
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METASTASIS , *COLON tumors , *CANCER patients , *CONFIDENCE intervals , *GENETIC polymorphisms , *META-analysis , *RESEARCH funding , *SURVIVAL analysis (Biometry) , *TREATMENT effectiveness , *DNA methylation , *DESCRIPTIVE statistics , *DNA demethylation , *ODDS ratio , *PROGNOSIS ,RECTUM tumors - Abstract
Abstract Background CpG island DNA hypermethylation and global DNA hypomethylation are hallmark characteristics of colorectal cancer (CRC). Therefore, we aim to explore the effect of genetic variations within the genes that regulate the DNA methylation and demethylation pathways on outcomes in patients with metastatic CRC (mCRC) treated with first-line therapy and enrolled in three independent, randomised, open-label clinical trials. Methods A total of 884 patients with mCRC enrolled in TRIBE, MAVERICC and FIRE-3 trials were included. Single-nucleotide polymorphisms (SNPs) within genes involved in DNA methylation and demethylation pathways were analysed. The prognostic value of each SNP across all treatment arms was quantified using the inverse-variance–weighted effect size, a meta-analysis approach implemented in the METASOFT software. Results In the meta-analysis, DNMT3A rs11681717 was significantly associated with overall survival (hazard ratio = 1.26; 95% confidence interval [CI] 1.08–1.46; P = 0.002; false discovery rate [FDR] = 0.016), accounting for seven tests in the DNA methylation pathway. In addition, there was suggestive evidence of association for ten-eleven translocation (TET) genes variance with tumour response (TET1 rs3814177, odds ratio [OR] = 0.76, 95% CI 0.59–0.97, P = 0.025, FDR = 0.087; TET3 rs7560668, OR = 1.44; 95% CI 1.10–1.89; P = 0.009; FDR = 0.062). Conclusions We showed that polymorphisms within the genes responsible for the DNA methylation and demethylation machineries are correlated with outcomes in patients with mCRC who were enrolled in three independent, randomised, open-label, phase II/III clinical trials. In addition, we demonstrated the feasibility of a meta-analysis approach to identify stronger and more convincing association between gene polymorphisms and outcome, potentially leading the way to a new method of analysis for similar data set. Highlights • Epigenetic alterations are hallmark characteristics of colorectal cancer (CRC). • The impact of single-nucleotide polymorphisms within methylation genes on metastatic CRC (mCRC) outcome has not been studied yet. • Eight hundred eighty-four patients with mCRC enrolled in TRIBE, MAVERICC and FIRE-3 trials were included. • Here, we observed that DNMT3A rs11681717 was significantly associated with worse overall survival. • We also showed the feasibility of a meta-analysis approach for this kind of data set. [ABSTRACT FROM AUTHOR]
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- 2019
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